The present invention relates to compounds that inhibit procollagen C-proteinase, pharmaceutical compositions containing them, methods for their use, and methods for preparing these compounds.
The collagens are integral components of connective tissue. At present nineteen types of collagens have been identified. The interstitial collagen types I, II and III are the major collagen components of tissue. These collagens are synthesized as procollagen precusor molecules having amino- and carboxy-terminal peptide extensions also known as pro-regions. These pro-regions are typically cleaved upon secretion of the procollagen molecule to give a mature collagen molecule which is capable of association into highly structured collagen fibers. (see, e.g., Fessler and Fessler, Annu. Rev. Biochem. 47, 129, (1978); Kivirikko et al., Extracellular Matrix Biochemistry (1984) and Kuhn, Structure and Function of Collagen Types (eds Mayne, R and Burgeson, R. E.), Academic Press, Inc., Orlando, Fla. pp 1-42 (1987).
Excessive collagen deposition is associated with a variety of fibrotic diseases such as interstitial pulmonary fibrosis, pericentral fibrosis, Symmers"" fibrosis, perimuscular fibrosis, kidney fibrosis, endocardial sclerosis, hepatitis, acute respiratory distress syndrome, arthritis, cystic fibrosis, surgical adhesions, tendon surgery, corneal scarring, scleroderma, chronic allograft rejection, hemodialysis shunt fibrosis and restenosis. These diseases are characterized by excessive deposits of fibrillar interstitial collagens that are resistant to proteolyic degradation thus leading to the symptoms of fibrosis. Therefore, inhibition of the pathological deposition of these collagens should help in the treatment of these diseases.
Recent studies suggest that procollagen C-proteinase is the essential enzyme that catalyzes the cleavage of the C-propeptide of types I, II and III collagens and therefore instrumental in the formation of functional collagen fibers ((see, Fertala et al., J. Biol. Chem., 269, 11584, (1994)). It would therefore be desirable to provide procollagen C-proteinase inhibitors and thereby provide a means of combating diseases mediated by excessive deposition of these collagens. This invention fulfills this and related needs.
In a first aspect, this invention provides hydroxamic acids selected from the group of compounds represented by Formula (I): 
wherein:
R1 and R4 are, independently of each other, hydrogen or alkyl;
R2 is:
(i) cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, heteroaralkenyl, heterocyclo or heterocycloalkyl; or
ii) -(alkylene)-B1xe2x80x94X where B1 is xe2x80x94Oxe2x80x94, xe2x80x94NR8xe2x80x94, xe2x80x94S(O)0-2, xe2x80x94Cxe2x95x90O, xe2x80x94CONR8xe2x80x94, xe2x80x94NR8CO2xe2x80x94, NR8SO2xe2x80x94 or xe2x80x94C(xe2x95x90NR8)NR8SO2xe2x80x94 (where R8 is H or alkyl), and X is cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; or
(iii) -(alkylene)-B1xe2x80x94X where B1 is xe2x80x94NR8COxe2x80x94 (where R8 is H or alkyl), and X is cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl; or
(iv) R2 and R3 form an alkylene or heteroalkylene chain; with the proviso that R2 does not contain an imidazole group.
R3 is hydrogen or alkyl;
R6 is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl;
R5 is:
(i) hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, heteroaralkenyl, heterocycloalkyl, heteroalkyl, or -(alkylene)-C(O)xe2x80x94X1 where X1 is alkyl, hydroxy, alkoxy, aryl, aralkyl, aryloxy, aralkyloxy, heteroaryl, heteroaryloxy, heteroaralkyloxy or NRxe2x80x2Rxe2x80x3 (where Rxe2x80x2 and Rxe2x80x3 are independently H or alkyl, or Rxe2x80x2and Rxe2x80x3 form an alkylene chain); or
(ii) R5 and R4 form an alkylene chain; or
(iii) R5 and R6 form an alkylene chain;
n is 0 or 1;
A is xe2x80x94N(R10)xe2x80x94(CH2)mxe2x80x94CH(R9)xe2x80x94C(xe2x95x90O)xe2x80x94 wherein:
m is an integer from 0-5 inclusive;
R9 is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, heteroalkyl, or -(alkylene)-C(O)xe2x80x94X1 where X1 is alkyl, hydroxy, alkoxy, aryl, aralkyl, aryloxy, aralkyloxy, heteroaryl, heteroaryloxy, heteroaralkyloxy or NRxe2x80x2Rxe2x80x3 (where Rxe2x80x2 and Rxe2x80x3 are independently H or alkyl, or Rxe2x80x2 and Rxe2x80x3 form an alkylene chain); and
R10 is hydrogen, alkyl, aralkyl or heteroaralkyl;
Z is Yxe2x80x94B2 wherein:
Y is alkylene or a bond; and
B2 is xe2x80x94COxe2x80x94, xe2x80x94OC(O)xe2x80x94,
with the proviso that when R2 is benzyl then Z is not xe2x80x94OC(O)xe2x80x94;
R7 is cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl;
or a pharmaceutically acceptable salt, prodrug, or isomer thereof.
In a second aspect, this invention provides a method of treatment of a disease in a mammal treatable by administration of a procollagen C-proteinase inhibitor selected from the group of compounds represented by Formula (I):
In a third aspect, this invention provides pharmaceutical compositions containing a therapeutically effective amount of a compound of Formula (I) or its pharmaceutically acceptable salt and a pharmaceutically acceptable excipient.
In a fourth aspect, this invention provides a method of treating disease by administering to a patient a selective inhibitor of procollagen-C-proteinase.
In a fifth aspect, this invention provides a method of preparing compounds of Formula (I).